In vivo visualisation of different modes of action of biological DMARDs inhibiting osteoclastic bone resorption.

Abstract

OBJECTIVES:

Osteoclasts play critical roles in inflammatory bone destruction. Precursor cell migration, cell differentiation, and functional cell activation are all in play. Biological disease-modifying antirheumatic drugs (DMARDs) have been shown to significantly inhibit both bone erosion as well as synovitis, although how such agents reduce osteoclastic bone destructionin vivo has not been fully explained. Here, we used an intravital time-lapse imaging technique to directly visualise mature osteoclasts and their precursors, and explored how different biological DMARDs acted in vivo.

METHODS:

Lipopolysaccharide (LPS) was injected into the calvarial periosteum of fluorescent reporter mice to induce inflammatory bone destruction. Time-lapse imaging was performed via intravital multiphoton microscopy 5 days after LPS injection. Biological DMARDs, including monoclonal antibodies (mAbs) against the interleukin (IL) 6 receptor (IL-6R) and tumour necrosis factor α (TNFα), or cytotoxic T-lymphocyte-associated protein 4 (CTLA4)-Ig, were intraperitoneally administered at the time of LPS injection. We determined CD80/86 expression levels in mature osteoclasts and their precursors by flow cytometry, quantitative PCR and immunohistochemistry.

RESULTS:

Of the biologicals tested, anti-IL-6R and anti-TNFα mAbs affected mature osteoclasts and switched bone-resorbing osteoclasts to non-resorbing cells. CTLA4-Ig had no action on mature osteoclasts but mobilised osteoclast precursors, eliminating their firm attachment to bone surfaces. In agreement with these results, CD80/86 (the target molecules of CTLA4-Ig) were prominently expressed only in osteoclast precursor cells, being suppressed during osteoclast maturation.

CONCLUSIONS:

Intravital imaging revealed that various biological DMARDs acted at specific therapeutic time points during osteoclastic bone destruction, with different efficacies. These results enable us to grasp the real modes of action of drugs, optimising the usage of drug regimens.

• Authors: Yoshinobu Matsuura, Junichi Kikuta, Yuika Kishi, Tetsuo Hasegawa, Daisuke Okuzaki, Toru Hirano, Masafumi Minoshima, Kazuya Kikuchi, Atsushi Kumanogoh, Masaru Ishii
• Journal: Annals of the rheumatic diseases (Ann Rheum Dis) Vol. 77 Issue 8 Pg. 1219-1225 (08 2018) ISSN: 1468-2060 [Electronic] England
• PMID: 29705743 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Chemical References

• Antirheumatic Agents
• B7-1 Antigen
• B7-2 Antigen
• Cd86 protein, mouse
• Receptors, Interleukin-6
• Tumor Necrosis Factor-alpha

Topics

• Animals
• Antirheumatic Agents (pharmacology, therapeutic use)
• B7-1 Antigen (metabolism)
• B7-2 Antigen (metabolism)
• Bone Resorption (immunology, pathology, prevention & control)
• Cell Differentiation (drug effects)
• Cell Movement (drug effects)
• Intravital Microscopy
• Mice, Inbred C57BL
• Mice, Transgenic
• Osteoclasts (drug effects, immunology, physiology)
• Receptors, Interleukin-6 (antagonists & inhibitors)
• Tumor Necrosis Factor-alpha (antagonists & inhibitors)